A disintegrin and metalloproteinase (hereinafter referred to as “ADAM”) is a disintegrin and metalloproteinase domain-containing multifunctional protein, and is known for having both adhesive and proteolytic properties in cell-cell and cell-matrix interactions. ADAM15 is a unique protein having an Arg-Gly-Asp (RGD) motif in its disintegrin-like domain. ADAM15 is expressed in smooth muscle cells, mesangial cells and endothelial cells. ADAM family involves in various biological processes such as fertilization, muscle development, nerve growth, and cytokine secretion (Blobel C P, et al.; Nature 1992. 356: 248-252.; Aitken, J. Nature 1992; 356: 196-197; Blobel C P, et al. J. Cell Biol. 1990; 111: 69-78.; White J M. Curr. Opin. Cell. Biol. 2003; 15: 598-606). It is known that the disintegrin-like domain known as EGF (Epidermal growth factor)-like domain of ADAM15, especially, specifically binds integrin beta chain (integrin beta 3) and binds Src family protein tyrosine kinase, and functions in the signal transmission and adhesion between cells. ADAM 15 protein is known for being associated with inflammatory diseases such as rheumatism and various diseases including breast cancer and prostate cancer, and further study is needed.
On the other hand, human skin is composed of the epidermis including the stratum corneum and dermis, and the connective tissue, and the stratum corneum is composed of layers of dead cells formed through a differentiation process of keratinocytes, basal cells in the epidermis, and plays a role in protecting the human body from the influence of outdoor environment. Furthermore, the dermis layer that is located in the skin is composed of fibrous proteins, collagen and elastin, and provides elasticity to the skin and serves to stay the skin tight, and the dermis layer has blood vessels and nerves and also contain mast cells that involve in allergic reactions, and natural moisturizing factors such as Na-PCA or hyaluronic acid.
The cause of skin wrinkle generation is largely classified into two: one is “intrinsic aging” comprising age-related changes in function of cells, namely, the unit that makes up the skin, and the other is “extrinsic aging” or aging related to outdoor environment, i.e., ultraviolet (UV) rays, air pollution, and stress. Photoaging, the prolonged exposure to UV, is the greatest cause of skin aging, and causes acute and chronic skin wound including skin cancer and wrinkle. This is classified into three: UVA (320-400 nm), UVB (290-320 nm) and UVC (200-290 nm), according to the wavelength ranges in solar light, and UVC is almost completely absorbed by the ozone layer, whereas UVA and UVB reach the Earth's surface and act as a fatal factor causing skin damage. It is known that UVB having shorter wavelengths, but higher intensity, than UVA penetrates the epidermis that rests on the dermis and damages keratinocytes and collagen fibers, consequently causing wrinkle generation, skin discoloration or skin cancer. Furthermore, recently it was discovered that interactions between cellular and extracellular matrix proteins (collagen, fibrillin, fibronectin) play an important role in the survival and growth of skin cell and reconstruction of tissue.
Burns are primarily caused by accidents, and can be classified into heat burns, electrical burns, chemical burns, radiation burns according to the cause. The severity of a burn is divided into first-, second-, third- and fourth-degree burns according to the burned width and depth, the contact time with the temperature of objects causing burns, and skin conditions. In second or higher degree burns, scar may be left behind and treatment in hospital is required.
First-degree burns cause skin redness and itching pain. They cause damage to the epidermis, the outermost layer of the skin layer, and swelling accompanied by pain and redness. The symptoms disappear in a few days, but superficial exfoliation and pigmentation may be left behind. After recovery, cicatrix (scar) does not remain. Sunburn is the most common example of first-degree burn.
Second-degree burns affect the epidermis and dermis, and cause redness, pain, swelling, and blisters in 24 hours after accidents. Second-degree burns may affect the sweat glands or pores. Severe burning sensation and pain occurs. Rupture of blisters leaves eroded areas and releases the secretion in large amounts. When the burned area is about 15% or more of the body surface area, special attention should be given. Second-degree burns are cured in a few weeks, but in many cases, pigmentation or depigmentation is left behind. When secondary infections occur, partial symptoms become severer and it takes longer to heal.
Third-degree burns affect the epidermis, dermis, and even subcutaneous fat, and the skin becomes darker or lighter in color, and blood vessels immediately beneath the skin surface are coagulated. Burned regions may be benumbed, but patients feel extremely severe pain and there is the death of skin tissue and structure, requiring a lot of time to treat, with scars left behind. In 2 weeks after accidents, scabs peel away and reveal ulcerated surface. Large quantities of fluids are secreted and bleeding is likely to occur, but third-degree burns are healed when new tissues gradually form, leading to regeneration of epidermis, with cicatrix left behind. When deep skin necrosis develops, or when secondary infections occur, healing is delayed and uneven cicatrix surface is created, resulting in keloid formation or deformation or movement disorders. When the burned area is 10% or more of the body surface area, special attention is required.
Fourth-degree burns involve carbonized and darkened tissues of burned regions, and extend through the skin layer to injure fatty layer, ligaments, fasciae, muscles, and even bone tissues. Fourth-degree burns primarily include high voltage electrical burns, and in some cases, deep dermal 2-3 degree burns may develop to fourth-degree burns when viral infection occurs. When the burned area ranges 20% or more, responses may occur all over the body; hypotension, shock, acute kidney dysfunction may occur due to excessive loss of body fluids, and wound infection or pneumonia, sepsis, and multiple organ dysfunction syndrome may occur later.
Burns treatment focus on the regeneration of skin and skin appendages, but currently developed technology does not provide a perfect treatment.
Glaucoma collectively means diseases that is caused in optic nerve including retinal plexus cells and have a form of optic nerve atrophy. Untreated glaucoma may eternally affect vision. In the past, glaucoma was defined as a disease that causes optic nerve damage and consequential visual impairment due to higher intraocular pressure than normal, but recently, it is reported that optic nerve damage of glaucoma is caused by many factors other than high intraocular pressure, and thus, glaucoma is defined as a progressive optic nerve syndrome causing characteristic changes of optic nerve and consequential visual impairment.
Glaucoma may be classified into open angle glaucoma, closed angle glaucoma, congenital glaucoma, secondary glaucoma, phacolytic glaucoma, pseudoexfoliation glaucoma, phacomorphic glaucoma, neovascular glaucoma, and steroid glaucoma, according to causes or syndromes.
In glaucoma patients, in the event that the intraocular pressure is not adjusted by drug treatment and laser treatment, or despite adequate drug treatment, visual impairment is found in vision examination and worsening sign of optic nerve changes of glaucoma is found in funduscopic examination, or when the use of drugs is disallowed due to adverse effects, surgical treatment is considered. Trabeculectomy is one of commonly used surgery methods. Trabeculectomy allows artificial drainage of aqueous humor through filtering blebs to reduce the intraocular pressure. The wound healing process and scar formation in the filtering blebs formed by surgery causes blockage of aqueous humor drainage pathway and gradually degrades the function of filtering blebs, resulting in surgery failure. Currently, to increase the long-term surgery success rate of trabeculectomy, antimetabolite, 5-fluorouracil (5-FU) or mitomycin C (MMC), is used as adjuvant treatment, and it resulted in a higher success rate of trabeculectomy but increased late complications, for example, low intraocular pressure, filtering bleb leaks, and filtering bleb-related infection. More recently, there is a report that OculusGen™ (OculusGen Biomedical Inc., Taipei, Taiwan) is used to provide a scaffold for growth of fibroblast in ‘ discretionally organized’ way, and allow ‘discretionally arranged fibroblasts’ to produce and arrange collagen in many directions around cells so that structure similar to the collagen structure found in normal tissue is formed, not collagen structure found in scar tissue, for use in trabeculectomy. However, there is a need for alternative solutions to treat glaucoma other than trabeculectomy.
Generally, the hair growth cycle has three stages: anagen, catagen, and telogen. Anagen is the active growth phase of hair and occupies the most of the hair growth life cycle. Catagen is characterized by apoptosis, and in this phase, hair is ready to fall off, and telogen is the resting or quiescent phase of hair follicles during which hair begins to fall, causing a noticeable loss of hair.
Alopecia or hair loss occurs when hair roots become weak and hair is thinned in repetitions of anagen-catagen-telogen, and eventually, hair becomes soft, fine and short. It is known that the cause of hair loss includes inherited factors, over-secretion of sexual hormone testosterone, reduced blood flow to follicles, over-secretion of sebum, stress, irregular food timings, air pollution, and excessive exposure to UV, and in most cases, many causes act in combination.
Alopecia is greatly classified into androgenetic alopecia, female pattern hair loss, alopecia areata, and hair loss caused by other causes. Androgenetic alopecia is a phenomenon appearing due to a male hormone, called testosterone, playing a role in promoting male sexual characteristics and causing muscles to grow and male organs to mature during adolescence, and when testosterone is converted to a more potent hormone dihydrotestosterone (DHT) by 5 α-reductase enzyme, the hormone acts on follicle dermal papilla cells to induce anagen-to-catagen transition in follicles, resulting in hair loss. Female pattern hair loss is usually due to low estosterone levels after menopause. Female pattern hair loss does not emerge on the frontal scalp and mainly proceeds over the mid scalp, dissimilar to androgenetic alopecia. Hair loss in women is less associated with 5 α-reductase than men. Thus, drugs which inhibit 5 α-reductase do not work for women experiencing hair loss after menopause. Alopecia areata is caused by autoimmune diseases, mental stress, or inherited factors. Alopecia areata represents round or oval patches of hair loss, and is characterized by tinea capitis or trichotillomania. The cause of alopecia areata is fundamentally different from androgenetic alopecia, and different treatment methods are used, for example, drugs to control adrenal cortex hormones are used, or minoxidil is applied to affected parts.
To solve the hair loss problem, various active ingredients having hair loss prevention and treatment effects and compositions including the same have been studied. The main or intended effect of this study includes an effect in maintaining hair thickness or thickening hair, an effect for induced early onset or prolonged anagen, an effect for delayed or shortened telogen release, an inhibitory effect of 5α-reductase activity, an effect on the promotion of blood circulation to hair follicles, a moisturizing effect, an anti-oxidation effect, a dandruff prevention effect, a sterilization effect, and an Extra-Cellular matrix (ECM) expression promotion effect.
The approved medication being used now is Minoxidil. Minoxidil was originally produced as an antihypertensive drug that helps the widening of smooth muscle blood vessels, but was developed as a drug to promote hair growth after discovery of its adverse effects, hair growth everywhere on the body (U.S. Pat. Nos. 4,596,812 and 4,139,619). Although its detailed scientific mechanism of action is not known, it is regarded that Minoxidil promotes hair growth through combination action of providing more blood flow to follicles. Based on this effect, Minoxidil was approved as over-the-counter medication by FDA, but adverse effects such as skin irritation, itching, redness, hair growth in unwanted part, and worsening of hair loss were reported, and also it should be continuously administered to maintain efficacy.